Cervical spinal cord injury (SCI) disrupts neural pathways to respiratory motor neurons, diminishing breathing capacity. Since even modest breathing impairment greatly increases susceptibility to life-threatening lung infections, restorin lost breathing capacity will improve the quality and duration of life. With funding from this MERIT Award, we discovered that repetitive acute intermittent hypoxia (rAIH) triggers plasticity in spared neural pathways to respiratory motor neurons, thereby restoring lost breathing capacity. We propose to extend these findings by addressing fundamental gaps in our knowledge concerning mechanisms of rAIH-induced functional recovery in rats with cervical SCI. The fundamental hypothesis guiding this proposal is that completely different cellular mechanisms underlie rAIH-induced functional recovery in early (<4 weeks) versus chronic SCI (>4 weeks). We propose that rAIH elicits plasticity via adenosinergic mechanisms in early SCI, but serotonin-dependent (adenosine-constrained) mechanisms in chronic SCI. This surprising idea will change the way we think about respiratory plasticity following SCI. Indeed, the realization that mechanisms giving rise to rAIH-induced plasticity and functional recovery are time-dependent will profoundly alter our ability to harness rAIH as a therapeutic intervention in humans with respiratory insufficiency due to chronic SCI. Since AIH-induced respiratory plasticity is impaired by systemic inflammation and constrained by cross-talk inhibition from competing mechanisms of phrenic motor facilitation, we hypothesize that functional outcomes may be improved by diminishing these factors in chronic (not early) SCI. We propose to investigate rAIH-induced functional recovery with a highly novel, multi-disciplinary approach including: 1) plethysmography to assess breathing capacity; 2) EMG telemetry of respiratory muscles; 3) flow cytometry to assess changes in identified respiratory motor neurons; 4) immuno-fluorescence to assess key proteins in situ; and 5) manipulation of respiratory motor neuron gene expression via RNA interference in vivo. Three specific aims are proposed to test the hypotheses that: 1) adenosine- (early) and serotonin-dependent (chronic) mechanisms dominate rAIH- induced functional recovery at different times post-injury; a corollary is that spinal adenosine 2A receptor inhibition augments rAIH-induced functional recovery in chronic (not early) SCI; 2) the contributions of different inspiratory muscles shift with time post-injury; and 3) systemic inflammation impairs rAIH-induced functional recovery in chronic (not early) SCI. Although rAIH has potential to be a safe, non-invasive treatment for SCI- induced respiratory impairment, any rational translation of this promising therapy will require detailed understanding of its underlying mechanisms, including complexities such as shifting mechanisms with time post-injury and factors that degrade its therapeutic efficacy. rAIH represents a promising new strategy to enhance function in patients with chronic SCI, where the prognosis for functional gains is bleak.